Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury

Yang, Ling; Greig, Nigel H.; Huang, Ya‐Fang; Hsieh, Tsung Hsun; Tweedie, David; Yu, Qian; Hoffer, Barry J.; Luo, Yu; Kao, Yu Chieh Jill; Wang, Jia Yi

doi:10.1016/j.nbd.2016.08.012

Cited by 37 publications

(44 citation statements)

References 82 publications

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“…Although best known as a tumor suppressor induced by DNA damage, several studies have documented p53 induction in patient tissue and in experimental models of a variety of chronic and acute neurodegenerative disorders (Culmsee and Mattson, 2005), which include Alzheimer's disease (de la Monte et al, 1997; Kitamura et al, 1997), Huntington’s disease (Bae et al, 2005), Parkinson's disease (Duan et al, 2002; Mogi et al, 2007; Qi et al, 2016), ALS (Martin, 2000; Ranganathan and Bowser, 2010) and traumatic brain injury (Yang et al, 2016). Interestingly, our results demonstrate that induction and nuclear accumulation of p53 are not sufficient to drive neurodegeneration in vivo .…”

Section: Discussionmentioning

confidence: 99%

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

et al. 2017

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Summary The hallmark of spinal muscular atrophy (SMA) – an inherited disease caused by ubiquitous deficiency in the SMN protein – is the selective degeneration of subsets of spinal motor neurons. Here we show that cell-autonomous activation of p53 occurs in vulnerable but not resistant motor neurons of SMA mice at pre-symptomatic stages. Moreover, pharmacological or genetic inhibition of p53 prevents motor neuron death, demonstrating that induction of p53 signaling drives neurodegeneration. At late disease stages, however, nuclear accumulation of p53 extends to resistant motor neurons and spinal interneurons but is not associated with cell death. Importantly, we identify phosphorylation of serine 18 as a specific post-translational modification of p53 that exclusively marks vulnerable SMA motor neurons and provide evidence that amino-terminal phosphorylation of p53 is required for the neurodegenerative process. Our findings indicate that distinct events induced by SMN deficiency converge on p53 to trigger selective death of vulnerable SMA motor neurons.

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Section: Discussionmentioning

confidence: 99%

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

et al. 2017

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“…The study on the role of SiO 2 in lung fibroblasts revealed that SiO 2 can induce pulmonary fibrosis, which is mediated by an increased expression of p53 and PUMA in cells. However, the activation and migration of SiO 2 ‐induced fibroblasts were antagonized after silencing p53 with p53 siRNA . The mRNA expression of p53 and the protein expression of PUMA were significantly increased in HepG2 cells after being treated with MC‐LR for 24 hours .…”

Section: Discussionmentioning

confidence: 96%

“…However, the activation and migration of SiO 2 -induced fibroblasts were antagonized after silencing p53 with p53 siRNA. 40,41 The mRNA expression of p53 and the protein expression of PUMA were significantly increased in HepG2 cells after being treated with MC-LR for 24 hours. 42 In addition, the study of zebrafish embryotoxicity induced by MC-LR also showed that MC-LR can induce a significant increase in the expression of p53 and bax protein in zebrafish embryos, suggesting that the p53-Bax-Bcl-2 pathway plays an important role in the MC-LR-induced embryotoxicity of zebrafish.…”

Section: Effect Of Pft-α On the Expression Of Apoptosisrelated Protmentioning

confidence: 99%

p53‐Dependent pathway and the opening of mPTP mediate the apoptosis of co‐cultured Sertoli‐germ cells induced by microcystin‐LR

Liu

Huang

et al. 2019

Environmental Toxicology

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Microcystin‐LR (MC‐LR), a potent endotoxin, can induce reproductive toxicity. In order to investigate the role and mechanisms of apoptosis (p53‐dependent and mitochondrial pathways) of germ cells induced by MC‐LR, the co‐cultured primary Sertoli‐germ cells from Sprague‐Dawley rats were used for the experiments. Expression levels of proteins, genes, and mitochondrial membrane potential (MMP) were obtained after exposing co‐cultured Sertoli‐germ cells to MC‐LR with or without the addition of the p53 inhibitor, pifithrin‐α (PFT‐α), and MMP inhibitor, cyclosporin A (CsA). Results indicated that MC‐LR could activate p53‐dependent pathway‐associated proteins in Sertoli‐germ cells, leading to a decrease in MMP (indicating the opening of mitochondrial permeability transition pore [mPTP] and the release of Cytochrome‐c [Cyt‐c]) from the mitochondria into the cytoplasm and eventually the induction of apoptosis. PFT‐α inhibited the expression ofp53, ameliorated the MMP of the co‐cultured Sertoli‐germ cells, and prevented the release of Cyt‐c from the mitochondria into the cytoplasm, which reduces the occurrence of apoptosis. Similarly, the decreased release of Cyt‐c from the mitochondria into the cytoplasm and the declined level of apoptosis in Sertoli‐germ cells induced by MC‐LR were observed after the addition of CsA. These results indicated that the apoptosis of the co‐cultured Sertoli‐germ cells induced by MC‐LR was mediated by the p53‐dependent pathway, with the involvement of the opening of mPTP.

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“…Regardless, it is tempting to speculate that treatments that could relieve telomere dysfunction or abrogate the p53 mediated stress response could potentially ameliorate patient outcomes. Pifithrin-α has already been shown to be an effective treatment to restore neuronal function in murine models of injury or stroke 100–102 . Significant future effort will be devoted to determining both whether telomere dysfunction is a common trigger for ID Syndromes, and whether telomere restoration could potentially help patients.…”

Section: Discussionmentioning

confidence: 99%

Loss of MECP2 leads to activation of p53 and neuronal senescence

Ohashi¹,

Allen²,

Lee³

et al. 2017

Preprint

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27To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic 28 lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient 29 fibroblasts with and without MECP2 expression in an attempt to recapitulate disease 30 phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression 31 changes including induction of a Senescence Associated Secretory Phenotype (SASP) 32 program. Patient derived Neurons made without MECP2 show signs of stress, including 33 induction of p53, and senescence. The induction of p53 appeared to affect dendritic 34 branching in Rett neurons, as p53 inhibition restored dendritic complexity. These 35 disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to 36 an increase in aspects of neuronal aging. 37 38 39 40 41 42 43 44 45 46Rett Syndrome is a disease associated with loss of function mutations in the gene 48 MECP2, which was originally identified as encoding a methylated DNA binding protein 1-49 3 . Patient symptoms include microcephaly, intellectual disability, facial dysmorphia, and 50 seizure activity 4,5 . Studies in murine models recapitulate many of the patient phenotypes 51 and have recently identified a role for MECP2 particularly in inhibitory neurons [6][7][8][9] . These 52 studies demonstrated that loss of MECP2 can lead to defects in transcription 10-12 , 53 dendritic branching 13 , nuclear size 3 , and AKT signaling 14 .54 55 MECP2 has also been described as a transcription factor with specific targets 10,11,13 , and 56 more broadly as either a transcriptional activator 14 or repressor [15][16][17][18] . However, despite 57 decades of research on MECP2, it is still unclear how mutations in this protein lead to 58 patient symptoms 3,14,[19][20][21] . To confirm findings made in other models and further study 59 these in a human system, some have turned to modeling Rett Syndrome in vitro by taking 60 advantage of Disease in a dish approaches. This involves making hiPSCs from patient 61 somatic cells, or using genome engineering to introduce mutations into WT human 62 pluripotent stem cells. In either case, the pluripotent stem cells created are then 63 differentiated toward the neural lineage, and then comparisons can be made between 64 cells that express MECP2 or lack it. 65 66 Some of these studies have even taken advantage of isogenic or congenic cells lines to 67 identify both transcriptional and electrophysiological effects of loss of MECP2 in human 68 4 in vitro models 14,22 . In the current study, we also sought to mitigate the effect of genetic 69 background and variability of differentiation by taking advantage of several congenic lines 70 of hiPSCs that either express the WT allele or the mutant allele leading to cells that 71 express or lack MECP2 23 . This allowed for detailed molecular analyses of hiPSCs, NPCs 72 and neurons with and without MECP2 under the same genetic background. In addition, 73 several lines were made and analyzed in each category to avoid vari...

show abstract

Post-traumatic administration of the p53 inactivator pifithrin-α oxygen analogue reduces hippocampal neuronal loss and improves cognitive deficits after experimental traumatic brain injury

Cited by 37 publications

References 82 publications

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

p53‐Dependent pathway and the opening of mPTP mediate the apoptosis of co‐cultured Sertoli‐germ cells induced by microcystin‐LR

Loss of MECP2 leads to activation of p53 and neuronal senescence

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